The impact of influenza infection is felt globally each year when the disease develops in approximately 20% of the world's population. Influenza A virus, in particular, represents a significant health risk to the public. This is due both to its ability to spread quickly within human populations and the high degree of mortality associated with infection. In the last century, three influenza A pandemics in 1918, 1957 and 1968 killed cumulatively over 50 million people. The highly pathogenic H5N1 and H1N1 strains of influenza A virus are emerging as the most likely cause of the world's next major influenza pandemic.
Influenza viruses belong to the family Orthomyxoviridae, and are divided into three (3) genera: Influenza A, Influenza B, and Influenza C. Influenza A can cause epidemics and pandemics in humans and may be transmitted through an animal intermediate host. Influenza B can cause epidemics and has no intermediate host. Influenza C does not occur in epidemics and causes mild disease.
Influenza A viruses are further classified based on the identity of two surface glycoproteins: hemagglutinin and neuraminidase contained in the viral envelope. Nine subtypes of influenza neuraminidases are known, N1 to N9, and sixteen subtypes of hemagglutinin are known, H1 to H16. Thus for instance, influenza A H5N1 refers to an influenza virus which contains the H5 subtype hemagglutinin and the N1 subtype neuraminidase.
Within the viral envelope, the central core contains the viral RNA genome, made up of seven or eight pieces of segmented negative-sense RNA. Each of these RNA segments is separately encapsidated by a nucleoprotein (NP) and associated with one copy of a viral RNA-dependent RNA polymerase. The viral polymerase complex is a heterotrimer composed of two basic proteins, PB1 and PB2, and a more acidic protein, PA. The polymerase and endonuclease activities are carried out by PB1. The PB2 subunit binds to the 5′ methylated cap of host-cell pre-mRNAs before they are cleaved to provide primers for viral mRNA synthesis.
Existing influenza medicines include oseltamivir (Tamiflu®) and zanamivir (Relenza). These function by inhibiting neuraminidase, resulting in the inhibition of the release of newly formed virions from the infected cells. However, there have been several documented cases of the emergence of resistance to these drugs by several different sub-strains of avian flu H5N1. Also, the FDA has recently issued a warning label for Tamiflu® after reports of serious psychiatric side-effects in patients receiving the drug, especially children. These factors suggest that there is a significant clinical need for new influenza drugs, with improved properties (including efficacy, selectivity and reduced sensitivity to resistance) relative to the currently marketed drugs.